1. Field of the Invention
This invention relates to novel heterocyclylcarbonyl derivatives of urea, to processes for making them, and to their use as agents for the dissolution of gallstones, and in particular of cholesterol gallstones.
2. Description of the Prior Art
Cholelithiasis, one of the most common diseases of Western civilization, is under intensive investigation to determine not only the physio-chemical changes in bile which lead to cholesterol gallstone formation, but also how gallstones, once formed, can be dissolved. An execellent summary of the current state of such efforts is presented by Bell in Gut, 15, 913-929 (1974).
Many attempts have been made to indirectly dissolve cholesterol gallstones by dietary manipulation or by oral administration of a compound so as to alter the composition of bile secreted by the liver and thus reverse the pathogenic process of cholelithiasis. Recently, prevention and even reversal of the pathogenic cholelithiasis process in man has been reported by the administration of chenodeoxycholic acid (U.S. Pat. Nos. 3,859,437 and 3,969,503, issued January 7, 1975 and July 13, 1976, respectively), a substance believed to inhibit synthesis of cholesterol in the body.
Various acyl derivatives of urea have been described as useful agents for lowering blood cholesterol and for other purposes. U.S. Pat. No. 4,014,876, issued Mar. 29, 1977, discloses a series of 1-(3-isoxazolylcarbonyl)ureas as hypoglycemic and/or blood free-fatty acid normalizing antidiabetic agents. Samejima, Yakugaku Zasshi, 80, 1706-12 (1960) (C.A. 55, 10439h, 1961) reports preparation of several 1-(nicotinoyl)urea derivatives as intermediates for further synthesis. Guttman, et al., J. Pharm. Sci., 56(11) 1423-7 (1967) describe 1,2-dihydro-1-methyl-2-oxoquinoxalinyl carbamyl urea, a base-catalyzed degradation product of 9-methylisoalloxazine.
U.S. Pat. No. 3,806,601, issued April 23, 1974, describes the use of bis(p-chlorophenoxy)acetylurea as a serum cholesterol and lipid lowering agent in adult animals suffering from hyperlipemia. However, a decrease in these levels by a given compound or compounds does not necessarily imply that reversal of the pathogenic process of cholelithiasis with indirect solubilization of cholesterol gallstones will occur. U.S. Pat. No. 3,245,878, issued Apr. 12, 1966, reports on several acyl(alkanoyl, aroyl)-3-benzyloxyureas as agents for lowering blood cholesterol.
South African Pat. No. 7,501,773, published Jan. 13, 1976, describes 1-furoyl-3-(3-chloro-4-methylphenyl)-2-thiourea, a compound useful for controlling the ripening of sugar cane. Several N-carbamoylpyrazinecarboxamides useful as diuretics are described in U.S. Pat. No. 3,345,372, issued Oct. 3, 1967.